Document Detail


Tetramethylphenylenediamine protects the isolated heart against ischaemia-induced apoptosis and reperfusion-induced necrosis.
MedLine Citation:
PMID:  21077848     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Cytochrome c when released from mitochondria into cytosol triggers assembly of the apoptosome resulting in caspase activation. Recent evidence suggests that reduced cytochrome c is unable to activate the caspase cascade. In this study, we investigated whether a chemical reductant of cytochrome c, N,N,N',N'-tetramethylphenylene-1,4-diamine (TMPD), which we have previously shown to block cytochrome c-induced caspase activation, could prevent ischaemia-induced apoptosis in the rat perfused heart.
EXPERIMENTAL APPROACH: The Langendorff-perfused rat hearts were pretreated with TMPD and subjected to stop-flow ischaemia or ischaemia/reperfusion. The activation of caspases (measured as DEVD-p-nitroanilide-cleaving activity), nuclear apoptosis of cardiomyocytes (measured by dUTP nick end labelling assay), mitochondrial and cytosolic levels of cytochrome c (measured spectrophotometrically and by elisa), and reperfusion-induced necrosis (measured as the activity of creatine kinase released into perfusate) were assessed.
KEY RESULTS: We found that perfusion of the hearts with TMPD strongly inhibited ischaemia- or ischaemia/reperfusion-induced activation of caspases and partially prevented nuclear apoptosis in cardiomyocytes. TMPD did not prevent ischaemia- or ischaemia/reperfusion-induced release of cytochrome c from mitochondria into cytosol. TMPD also inhibited ischaemia/reperfusion-induced necrosis.
CONCLUSIONS AND IMPLICATIONS: These results suggest that TMPD or related molecules might be used to protect the heart against damage induced by ischaemia/reperfusion. The mechanism of this protective effect of TMPD probably involves electron reduction of cytochrome c (without decreasing its release) which then inhibits the activation of caspases.
Authors:
Jurgita Barauskaite; Regina Grybauskiene; Ramune Morkuniene; Vilmante Borutaite; Guy C Brown
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  162     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-01-28     Completed Date:  2011-05-06     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1136-42     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Affiliation:
Institute for Biomedical Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects
Cardiotonic Agents / pharmacology*
Caspases / metabolism
Cytochromes c / metabolism
Cytosol / metabolism
Enzyme Activation / drug effects
Male
Mitochondria, Heart / drug effects,  metabolism
Myocardial Reperfusion Injury / metabolism,  pathology,  prevention & control*
Necrosis / prevention & control
Rats
Rats, Wistar
Tetramethylphenylenediamine / pharmacology*
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 27215-51-6/Tetramethylphenylenediamine; 9007-43-6/Cytochromes c; EC 3.4.22.-/Caspases
Comments/Corrections

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